Dual-targeted Drug Delivery System With High Drug Loading Based On Magnetic Nanoparticles

Magnetic nanoparticles are biocompatible, biodegradable, conveniently adjustable, controlled by additional magnetic field, etc., so that they have drawn great attention and been widely applied in the field of biomedicine. According to the need of targeted therapeutics for cancer, dual-targeted drug delivery systems with high drug loading based on magnetic nanoparticles were studied in this paper. Several aspects are included:First, through co-precipitation method and sol-gel method, both protected amino and carboxyl modified multi functional magnetic nanoparticles Fe3O4@SiO2@RR’ (DMP) with a core-shell structure was designed and synthesized. Results show, DMP with a diameter between 40-60 nm, has a typical core-shell structure, good dispersity, superparamagnetic property and wide feasibility. It can couple different bioactive molecules (e.g., therapeutic drugs, fluorescent groups) and be used in many biomedical applications.Second, using a novel triplex "armed" multifunctional reagent, tris-succinimidyl aminotriacetate (TSAT), a functional group on DMP can make DMP couple with doxorubicin (DOX) in a ratio of one-to-two, DOX can be can be efficiently loaded on DMP. On the basis of high drug loading, another functional group on DMP can make c(RGDyK) peptide conjugated on DMP. Therefore, the dual targeted drug delivery system R-TSAT-DMP with high drug loading and magnetic-integrin αvβ3 targeting was synthesized. Results demonstrate that R-TSAT-DMP has good dispersity, stability, superparamagnetic property and high drug loading. R-TSAT-DMP is sensitive to pH for drug release. Compared with TSAT-DMP without c(RGDyK) peptide, R-TSAT-DMP exhibits increased uptake by integrin αvβ3 overexpressed tumor cells U87MG and displays higher tumor cell cytotoxicity.Third, using a novel multi "armed" multifunctional reagent Poly-L-glutamic acid (PLGA), magnetic nanoparticles can conjugat anticancer drug DOX in a ratio of one-to-multi, with higher drug loading. Different ligand (such as c(RGDyK) peptide, transferrin) are coupled on magnetic nanoparticles in a different chemical way, the dual targeted drug delivery systems with high drug loading(R-PLGA-DMP and Tf-PLGA-DMP) were successfully synthesized. Results demonstrate that R-PLGA-DMP and Tf-PLGA-DMP have diameter of 80-90 nm, good dispersity, narrow size distribution, superparamagnetic property, high drug loading and targeting. R-PLGA-DMP and Tf-PLGA-DMP are sensitive to pH for drug release. Compared with PLGA-DMP without c(RGDyK) peptide and Tf, R-PLGA-DMP and Tf-PLGA-DMP exhibit separately increased uptake by integrin αvβ3 overexpressed tumor cells U87MG and transferrin receptor overexpressed tumor cells (the Henrietta Lacks strain of cancer cells (HeLa) and human leukemia cell line K562 carcinoma cells) and both display higher tumor cell cytotoxicity. Through integrin αvβ3 and TfR mediated, R-PLGA-DMP and Tf-PLGA-DMP can target to tumor cells and achieve the goal of improving therapeutic efficiency, reducing side effect, and restricting targeted drug delivery.The aboved studies provide a new way for magnetic nano drug delivery systems to solove general problems such as low drug loading, weak targeting etc., and a novel technological basis for further clinic application.